Verrucous gastritis-like lesion in intramucosal Helicobacter pylori-uninfected signet ring cell carcinoma with poorly differentiated adenocarcinoma.

In Japan, accessible Helicobacter pylori (Hp) eradication therapy is associated with an increase in the prevalence of gastric cancers (GCs) in Hp uninfected stomachs. Signet ring cell carcinoma (SRCC) is the most common of these GCs. Intramucosal SRCC with poorly differentiated adenocarcinoma (PDA) occurring in Hp uninfected gastric mucosa is rare; furthermore, many Hp uninfected pure SRCCs exhibit discoloration and flat or slightly depressed lesions, and morphological elevation is relatively rare. We report a case of intramucosal SRCC with PDA with an elevated, verrucous gastritis-like lesion in a 57-year-old male patient. In the present case, the PDA area showed dense tumor cell growth and coexisting desmoplastic and fibrotic reactions. Histopathology and immunohistochemical staining identified extensive fibromuscular obliteration with smooth muscle bundles extending from the muscularis mucosa into the lamina propria. The patient underwent curative endoscopic submucosal dissection. The reporting and analysis of such rare cases may lead to a better understanding of the characteristics of advanced Hp uninfected GCs.

Is there any relationship between Helicobacter pylori infection and human epidermal growth factor receptor 2 expression in gastric cancer?

PURPOSE: Helicobacter pylori(HP) is a significant causative agent of gastric cancer (GC). However, the underlying mechanisms involved in its pathogenesis and association with oncoproteins are unclear. The aim of the present study was to evaluate the relationship between HP infection and human epidermal growth factor receptor 2 (HER2) expression in GC patients. MATERIALS AND METHODS: Surgery (173) or endoscopic biopsy (35) specimen of 208 patients diagnosed with GC was evaluated for the presence of HER2 and HP. HER2 expression was assessed by fluorescence in situ hybridization (FISH) method, whereas HP status was evaluated histologically. Giemsa stain was used to identify HP status, in case HP could not be recognized in routine H and E-stained sections despite careful examination. RESULTS: The median age was 63 years (27-91), and most patients were male (male/female: 149/59). Of all the 208 patients, HP was positive in 87 (41.8%) and negative in 121 (58.2%) patients. FISH positivity for HER2 was observed in 41 (19.7%) patients, whereas FISH negativity was observed in 167 (80.3%) patients. According to the Chi-square test, patient distribution was 21 in HER2-positive HP-negative group, 20 in HER2-positive HP-positive group, 100 in HER2-negative HP-negative group, and 67 in HER2-negative HP-positive group. No correlation was found between HP and HER2 status (P = 0.314). HP positivity had significant effect on median overall survival (27.4 vs. 12.9 months, P = 0.046). CONCLUSIONS: Our results suggest that there is no relationship between HP infection and HER2 status in patients with GC.

Whole Genome Sequencing Reveals Virulence Potentials of Helicobacter pylori Strain KE21 Isolated from a Kenyan Patient with Gastric Signet Ring Cell Carcinoma.

Helicobacter pylori (H.pylori) infection is etiologically associated with severe diseases including gastric cancer; but its pathogenicity is deeply shaped by the exceptional genomic diversification and geographic variation of the species. The clinical relevance of strains colonizing Africa is still debated. This study aimed to explore genomic features and virulence potentials of H. pylori KE21, a typical African strain isolated from a native Kenyan patient diagnosed with a gastric cancer. A high-quality circular genome assembly of 1,648,327 bp (1590 genes) obtained as a hybrid of Illumina Miseq short reads and Oxford Nanopore MinION long reads, clustered within hpAfrica1 population. This genome revealed a virulome and a mobilome encoding more than hundred features potentiating a successful colonization, persistent infection, and enhanced disease pathogenesis. Furthermore, through an experimental infection of gastric epithelial cell lines, strain KE21 showed the ability to promote interleukin-8 production and to induce cellular alterations resulting from the injection of a functional CagA oncogene protein into the cells. This study shows that strain KE21 is potentially virulent and can trigger oncogenic pathways in gastric epithelial cells. Expended genomic and clinical explorations are required to evaluate the epidemiological importance of H. pylori infection and its putative complications in the study population.

Is Proximal Gastric Cancer A Different Entity From Distal Gastric Cancer? Anatomical Site Distribution Of Signet Ring Cell Carcinoma And Its Association With Helicobacter Pylori Infection.

BACKGROUND: Despite many known variables affecting the outcome, little is known about the impact of histology on the location of tumour and outcomes. The objective of our study was to describe pattern of gastric cancer at single centre and association with H. Pylori and Signet ring cell variant with site of tumour in stomach. METHODS: This was a cross sectional study conducted at the Department of Surgery of Aga Khan University Hospital, Karachi, Pakistan. A total of 105 patients who underwent surgery for gastric adenocarcinoma were classified to have a proximal, distal or whole stomach cancer. An association was determined between the tumour histology and helicobacter pylori infection with the location of tumour in the stomach. RESULTS: Proximal gastric cancer was present in 27 (25.7%) patients and distal gastric cancer was present in 69 (65.7%) patients. There were 9 (8.6%) patients in whom tumour involved the whole stomach. Fifty-two patients (49.5%) had signet ring cell variant of gastric carcinoma and these patients were more like to have higher grade and advanced stage. Further analysis showed that that odds of proximal gastric tumour to have signet ring cell histopathology was 3.22 as compared to distal gastric tumour (p=0.017). Helicobacter Pylori infection status did not have any significant association with either grade of tumour or stage at the time of presentation. CONCLUSIONS: Despite limitations our data suggests that proximal gastric cancer may be biologically different from distal gastric cancers in terms of frequency of signet ring cell histology.

Gastric Adenocarcinomas and Signet-Ring Cell Carcinoma: Unraveling Gastric Cancer Complexity through Microbiome Analysis-Deepening Heterogeneity for a Personalized Therapy.

Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. With the advances of the omic studies, a heterogeneous GC landscape has been revealed, with significant molecular diversity. Given the multifaceted nature of GC, identification of different patient subsets with prognostic and/or predictive outcomes is a key aspect to allow tailoring of specific treatments. Recently, the involvement of the microbiota in gastric carcinogenesis has been described. To deepen this aspect, we compared microbiota composition in signet-ring cell carcinoma (SRCC) and adenocarcinoma (ADC), two distinct GC subtypes. To this purpose, 10 ADC and 10 SRCC and their paired non-tumor (PNT) counterparts were evaluated for microbiota composition through 16S rRNA analysis. Weighted and unweighted UniFrac and Bray-Curtis dissimilarity showed significant community-level separation between ADC and SRCC. Through the LEfSe (linear discriminant analysis coupled with effect size) tool, we identified potential microbial biomarkers associated with GC subtypes. In particular, SRCCs were significantly enriched in the phyla Fusobacteria, Bacteroidetes, Patescibacteria, whereas in the ADC type, Proteobacteria and Acidobacteria phyla were found. Overall, our data add new insights into GC heterogeneity and may contribute to deepening the GC classification.

The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome.

Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74-2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16-3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer.

Characterization of Helicobacter pylori-Naïve Early Gastric Cancers.

AIM: Helicobacter pylori-naïve gastric cancers(GCs) have not been well documented. We aimed to characterize early H. pylori-naïve GCs. SUBJECTS AND METHODS: Of 666 patients with GC resected by endoscopic submucosal dissection, H. pylori-naïve patients were extracted according to the definition: no H. pylori eradication history, negative for serum H. pylori-antibody and current H. pylori-infection tests, and no gastric atrophy by pepsinogen (PG) test, endoscopy, and histology. RESULTS: It was found that 16 GCs were H. pylori-naïve, and classified into undifferentiated and differentiated type adenocarcinoma. All 9 undifferentiated type GCs were pale, depressed, mucosal pure signet ring cell adenocarcinoma except one of them and 7 differentiated type GCs were classified into 3 fundic gland type GCs and 4 foveolar type GCs. All fundic gland type GCs positive for PG-1 were cardia small submucosal tumor (SMT)-like protrusions with dilated vessels on the surface. All 4 foveolar type GCs were composed of dysplastic clear cells resembling foveolar epithelium, negative for PG-1 but positive for mucin 6 (MUC6) and MUC5AC. Endoscopically, all were laterally spreading elevations with papillary or villous surface. CONCLUSIONS: H. pylori-naïve GCs were infrequent at 2.5%, and classified into 3 types: a small pale depression of signet ring cell adenocarcinoma, a small SMT-like protrusion of fundic gland type GC, and a large laterally spreading elevation of foveolar type GC.

Distribution of gastric carcinoma in an area with a high prevalence of Helicobacter pylori.

BACKGROUND/AIMS: South Asia is an enigma for gastric cancer (GC) because it is a low risk region with a high prevalence of Helicobacter pylori (H. pylori) infections. We evaluated the trend of GC clinical presentation and risk factors in patients with dyspeptic symptoms. MATERIALS AND METHODS: The medical records of patients, coded by the international classification of diseases (ICD-10-CM, 2015, Diagnosis Code C16.9) for malignancies of stomach diagnosed by esophagogastroduodenoscopy (EGD) and histopathology, were studied. RESULTS: 394 GC cases with a mean age of 54±15 years, range of 18 to 88, were analyzed. 256 (65%) were male. Distal non-cardiac and cardiac tumors were 302 (77%) and 92 (23%) cases, respectively. The WHO classification of GC defined 222 (56%) cases as intestinal type adenocarcinoma, 68 (17%) cases as signet ring cell carcinoma (SRC), 62 (16%) cases as diffuse type and 42 (11%) cases as B cell non-Hodgkin lymphoma. The co-morbid conditions associated with GC were H. pylori infection (positive in 246 (62%) cases), diabetes mellitus type 2 (in 90 (23%) cases), and cigarette smoking (in 94 (24%) cases). Of the male patients, 88 (34%) (p<0.001) were smokers. Body mass index was abnormal in all age groups and in both sexes. Cardiac regions for GC were more common in the 46- to 60-year old age range and in males. Diffuse GC was seen in all age groups but there were significantly more common in the 18- to 45-year old age range. Gastric non-Hodgkin's lymphoma was seen at an early age of 18-45 years in 14(12%) and a later of 61-88 years in 20 (15%). CONCLUSION: Intestinal type GC is common at all ages but SRC and diffuse GC are more common in patients less than 50 years old. SRC and diffuse GC were not specific to the elderly in our study population.

Biological behavior of the intramucosal Helicobacter pylori-negative undifferentiated-type early gastric cancer: comparison with Helicobacter pylori-positive early gastric cancer.

BACKGROUND: The differences in the growth morphology, proliferative ability, and background mucosa of the cancer between Helicobacter pylori (HP)-positive (HP+) gastric cancer (GC) and HP-negative (HP-) GC are still unclear. To clarify the differences, we compared the characteristics of the two types of cancer. METHODS: Of the 91 patients with undifferentiated-type early GC who underwent endoscopic treatment at our hospital between August 2005 and April 2011, 23 HP- GC patients (all of whom had signet ring cell carcinoma measuring 20 mm or less in diameter) and 46 HP+ GC patients with signet ring cell carcinoma measuring 20 mm or less in diameter (out of a total of 68 HP+ GC patients) were enrolled in this study. Endoscopic atrophy and background mucosa were classified according to the updated Sydney system. The proliferative capacity of the cancer was assessed by examining the MIB-1 labeling index. RESULTS: With regard to the growth in the mucosal layer, the proportion of patients with cancer confined to the proliferative zone was significantly higher in the HP- GC group. Moderate or severer atrophy, intestinal metaplasia, mononuclear cell infiltration, and neutrophil infiltration according to the updated Sydney system were significantly commoner in the HP+ GC patients. Also, the MIB-1 labeling index was significantly higher in the HP+ GC group. CONCLUSION: HP+ GC appeared to show a higher proliferative capacity, more extensive spread, and more rapid progression, and inflammation associated with HP infection was suggested to be involved in the proliferation of this type of GC.

[Clinical and morphological features in a case of recent gastric carcinoma (the signet ring cell carcinoma type)]. / Particularitati clinico-morfologice într-un caz de carcinom gastric incipient (tipul de carcinom în inel cu pecete).

The article presents the case of a male patient, hospitalized due to severe pain in the upper abdomen area, nausea, and vomiting. The patient was diagnosed with surgical acute abdomen, for which emergency surgery is performed. Upon penetration into the peritoneal cavity, stomach inspection shows at the medio-gastric level, on the greater curvature, a callous gastric ulcer, with a central perforation. A large excision is decided up to the healthy (normal) gastric tissue, and the resulting pieces are sent to the pathological anatomy laboratory. The histopathological exam reveals signet ring cell recent gastric carcinoma. The biopsy performed 1 month after surgery, prelevated from the antropyloric zone, reveals antropyloric gastritis with moderate activity and Helicobacter pylori positive. Due to the fact that such cases when this gastric cancer type is diagnosed in recent stages are extremely rare, we considered it useful to present it and look into its macroscopic and microscopic aspects, as well as into the differentiating diagnosis.

Relationship between H.Pylori infection and clinicopathological features and prognosis of gastric cancer.

BACKGROUND: Aimed to assess the relationship between H.Pylori and the clinicopathological features and prognosis of gastric cancer by quantitative detection of H.Pylori. METHODS: 157 patients were enrolled, all patients had a record of clinicopathological parameters. Specimens including the tumor and non-neoplastic were detected for H.Pylori by Real-Time PCR and analyzed clinical data retrospectively. Variables independently affecting prognosis were investigated by means of multivariate analysis using the Cox proportional hazards model. RESULTS: H.Pylori infection was greater in non-neoplastic tissue than the tumor tissue (p < 0.05), H.Pylori infection and its copies were related to the tumor site and N staging (p < 0.05). Overall survival (OS) in all 157 patients has no correlation with the H.Pylori infection status (p = 0.715). As to the patients who underwent a curative surgery, relapse-free survival (RFS) has no correlation with the H.Pylori infection status (p = 0.639). Among the H.Pylori positive patients, OS and RFS of those with higher copies were longer than in patients with low copies, but there was no significant statistical difference. CONCLUSIONS: H.Pylori infection status and its copies were related to N staging. The OS and RFS in patients with positive H.Pylori status has no significant difference from the patients with negative H.Pylori status.

Clinicopathological features and prognostic factors of proximal gastric carcinoma in a population with high Helicobacter pylori prevalence: a single-center, large-volume study in Korea.

BACKGROUND: The incidence of gastric cancers has fallen in recent decades. However, a substantial reduction in Helicobacter pylori prevalence and a substantial increase in the incidence of proximal gastric cancer (PGC) have been observed in the West and Japan, but not in other East Asian countries. The purpose of this large-volume study was to analyze prevalence, clinicopathological features, and prognosis of PGC compared with other types of gastric cancer in Korea, where there is high incidence of H. pylori infection. METHODS: Between 2000 and 2005, a total of 3,193 patients were enrolled. We analyzed clinicopathological features and survival outcomes. RESULTS: Chronological analysis showed increasing incidence of PGC over the study period. PGC patients were younger and had higher incidence of Bormann types III and IV than did distal gastric cancer (DGC) patients. Also, PGC was associated with a significantly higher proportion of poorly differentiated type, T3 and T4 stage, and positive lymph nodes compared with DGC. Peritoneal and other distant metastases were more common in PGC group than in DGC group. The 5-year survival rate was significantly lower in PGC than in DGC group, regardless of curative resection. Also, the N0 and N1 category significantly influenced the 5-year survival rate. Tumor-node-metastasis (TNM) stage, hepatic metastasis, and curative resection were significant prognostic factors in PGC patients. CONCLUSIONS: PGC has increased in incidence with the respective decline in H. pylori prevalence in Korea. Survival was worse for patients with PGC than for those with DGC, regardless of curative respectability. PGC is often diagnosed at more advanced stage than other gastric cancers, and therefore early detection is critical for successful treatment.

Relationship of p53 and Helicobacter pylori to clinicopathological features of human remnant stomach cancer after gastric surgery for primary gastric cancer.

The purpose of this study was to evaluate the biological features of gastric cancer of the remnant stomach (RSC). Twenty-one patients underwent resection of the remnant stomach for RSC and were divided into two groups: the RSCB group consisted of 11 patients who underwent distal gastrectomy for benign disease and the RSCM group consisted of 10 patients who underwent gastrectomy for primary gastric cancer. The interval between primary surgery and the appearance of gastric cancer in the remnant stomach was significantly shorter in the RSCM group than in the RSCB group. Invasion of adjacent organs was more frequent in the RSCM group than in the RSCB group and the Ki-67 labeling index of the tumors was significantly higher in the former group. Furthermore, p53 overexpression by tumors was almost twice as common in the RSCM group as in the RSCB group. Although there was no significant difference of the H. pylori positivity between the two groups, the rate for both groups was higher than reported in previous studies. Mutation of p53 may play an important role in the high proliferative activity of tumors in the RSCM group and H. pylori infection may be closely related to carcinogenesis in patients with RSC.

Aspirin protects against gastric cancer: results of a case-control study from Moscow, Russia.

A case-control study of stomach cancer which includes 448 cases and 610 hospital controls has been conducted in Moscow, Russia. Information on life-style habits, such as smoking, alcohol consumption, diet, medical history and use of different medications including aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) was collected using a self-administered structured questionnaire. Venous blood was drawn from 361 cases and 441 controls. A serological test for Helicobacter pylori immunoglobulin G was performed to detect infected individuals. Use of aspirin and other NSAIDs was associated with protection against cancer of the stomach (OR = 0.60, 95% CI 0.41-0.90). Analysis by subsite revealed that aspirin did not affect the risk of cancer of the gastric cardia but had a protective effect for non-cardia gastric cancer. The OR associated with use of aspirin adjusted for age and education for both sexes combined was 0.49 (95% CI 0.31-0.77). A decrease in relative risk was statistically significant for men (OR = 0.48, 95% CI 0.25-0.92) and women (OR = 0.52, 95% CI 0.28-0.97). Controlling for major risk factors did not attenuate the reduction in risk. The observed associations were also present in individuals who were H. pylori immunoglobulin G-positive. There was no reduction in risk associated with aspirin and/or non-aspirin NSAIDs among non-infected subjects.

Helicobacter pylori infection in patients with early gastric cancer by the endoscopic phenol red test.

BACKGROUND: An endoscopic procedure that uses a pH indicator called phenol red to assess Helicobacter pylori infected gastric mucosa has recently been developed. This test makes it possible to take biopsy specimens from H pylori infected areas. AIM: This test was applied to patients with early gastric cancers to clarify the role of H pylori in gastric carcinogenesis. SUBJECTS: Sixty five patients with early gastric cancer (50 with differentiated adenocarcinoma and 15 with undifferentiated adenocarcinoma). METHODS: Patients with early gastric cancer underwent the endoscopic phenol red test before their operation. In this test, areas infected with H pylori can be observed as "coloured" areas where phenol red was turned from yellow to red. RESULTS: H pylori infection was significantly (p < 0.001) more frequent in patients with differentiated adenocarcinomas than in those with undifferentiated adenocarcinomas. Differentiated adenocarcinomas were usually located in areas of mucosa infected with H pylori, but undifferentiated adenocarcinomas were frequently located in non-infected areas. CONCLUSION: H pylori may be a strong risk factor for differentiated early gastric cancer.

Epstein-Barr virus and gastric remnant cancer.

BACKGROUND: Carcinoma arising in the gastric remnant many years after partial gastrectomy for benign disease, referred to as gastric remnant cancer (GRC) is well known, and many causal explanations have been proposed. Elsewhere, Epstein-Barr virus (EBV) involvement has been demonstrated in a small but significant fraction of gastric cancers, and evidence has been presented suggesting that, in positive cases, EBV may have played a causal role. The present report is concerned with EBV involvement in GRC in particular. METHODS: Paraffin sections from 48 cases of GRC were studied by EBER-1 in situ hybridization. RESULTS: Thirteen cases (27.1%) showed uniform hybridized signals restricted to the carcinoma cells in contrast to no hybridization in the normal mucosa, intestinal metaplasia, or hyperplastic epithelium. The prevalence of EBV involvement in GRC was significantly higher (P < 0.0001) than in gastric carcinomas from 1825 nonremnant cases; the difference remained highly significant even when the comparison was restricted to nonremnant cancers arising in the cardia and middle stomach, for which EBV-positive rates were highest. CONCLUSION: The EBV may play an important role in the carcinogenesis of GRC.